Project Summary/Abstract There is an urgent need to find effective preclinical Alzheimer's disease (AD) treatments as quickly as possible. We established the Alzheimer's Prevention Initiative (API) to help launch a new era in AD prevention research, evaluating promising investigational preclinical AD treatments in people who, based on their genetic background and age, are at extremely high risk of progression to the clinical stages of AD, and helping to establish the biomarker and cognitive endpoints and accelerated regulatory approval pathway needed to rapidly evaluate new treatments. Our original API autosomal dominant AD (ADAD) grant proposed to prepare for and conduct the first stage of a 5-year, randomized, double-blind, placebo-controlled trial of an anti-amyloid agent in 200 cognitively unimpaired Presenilin 1 (PSEN1) E280A mutation carriers and placebo treated in 100 non- carriers (NC) from the world's largest ADAD kindred in Colombia. Outcomes include a sensitive composite cognitive endpoint and the best established brain imaging and cerebrospinal fluid (CSF) biomarkers of AD. Other goals are to clarify whether the treatment's biomarker effects are reasonably likely to predict later clinical benefit and help qualify them as surrogate endpoints under the FDA's accelerated approval pathway and provide a better test of the amyloid hypothesis. The grant received an outstanding priority score in 2012, permitted us to select our industry partner, Genentech, and its promising anti-amyloid antibody, crenezumab, garner $15M from philanthropy and the majority of funding from Genentech, and establish a novel agreement to share data and biological samples after the trial. Our subsequent proposal for another preclinical trial of both an active immunotherapy against amyloid and a medication to reduce its production (a BACE inhibitor) in cognitively unimpaired APOE4 homozygotes also received an outstanding priority score and secured NIH, Novartis/Amgen, and philanthropic support. API has created exceptionally large registries along the way to support enrollment in these and other trials. Our API ADAD trial was launched in 2013 and is going well; enrollment is expected to end in late 2016 and the trial will end in 2021. Our original aims were to prepare for and launch the first stage of this preclinical ADAD/biomarker development trial; clarify whether crenezumab's biomarker effects are related to a subsequent clinical benefit, explore the extent to which baseline biomarkers are associated with a differential response to treatment or subsequent cognitive decline in the absence of treatment; and eventually create a user- friendly public resource of preclinical AD trial data and biological samples after the trial is over. Our Current API ADAD Grant Aims are to 1) address the original aims, 2) Extend blinded treatment for those enrolled earliest in the to increase power to detect cognitive benefit, complete the trial, and address the original aims in a manner that provides the greatest benefit to the field; 3) Acquire tau PET images at the participants' 30 and 60 month visits and clarify their ability to predict clinical benefit and course; 4) Provide a secure and robust data repository along with the data search and visualization tools to support the most productive, prevalent, and appropriate use of data after the trial is over; and 5) Establish the infrastructure needed to share biological samples in the most productive and appropriate way. The proposed grant will help API investigators oversee the trial until its completion, analyze and report the data, incorporate and clarify the theragnostic value of tau PET images, and develop the infrastructure to share data and biological samples, aims that will not be funded by Genentech (nor our new APAI ADAD partner, Roche). This is an extremely inclusive project, having been vetted by leading academic and community stakeholder advisors, and representatives from the NIA, FDA, European Medicines Agency, and pharmaceutical research companies.